Dentate Gyrus Local Circuit is Implicated in Learning Under Stress--a Role for Neurofascin.

The inhibitory synapses at the axon initial segment (AIS) of dentate gyrus granular cells are almost exclusively innervated by the axo-axonic chandelier interneurons. However, the role of chandelier neurons in local circuitry is poorly understood and controversially discussed. The cell adhesion molecule neurofascin is specifically expressed at the AIS. It is crucially required for the stabilization of axo-axonic synapses. Knockdown of neurofascin is therefore a convenient tool to interfere with chandelier input at the AIS of granular neurons of the dentate gyrus. In the current study, feedback and feedforward inhibition of granule cells was measured in the dentate gyrus after knockdown of neurofascin and concomitant reduction of axo-axonic input. Results show increased feedback inhibition as a result of neurofascin knockdown, while feedforward inhibition remained unaffected. This suggests that chandelier neurons are predominantly involved in feedback inhibition. Neurofascin knockdown rats also exhibited impaired learning under stress in the two-way shuttle avoidance task. Remarkably, this learning impairment was not accompanied by differences in electrophysiological measurements of dentate gyrus LTP. This indicates that the local circuit may be involved in (certain types) of learning.

Long-term effects of controllability or the lack of it on coping abilities and stress resilience in the rat.

Findings suggest that stress-induced impaired learning and coping abilities may be attributed more to the psychological nature of the stressor, rather than its physical properties. It has been proposed that establishing controllability over stressors can ameliorate some of its effects on cognition and behavior. Gaining controllability was suggested to be associated with the development of stress resilience. Based on repeated exposure to the two-way shuttle avoidance task, we previously developed and validated a behavioral task that leads to a strict dissociation between gaining controllability (to the level that the associated fear is significantly reduced) and a fearful state of uncontrollability. Employing this protocol, we investigated here the impact of gaining or failing to gain emotional controllability on indices of anxiety and depression and on subsequent abilities to cope with positively or negatively reinforcing learning experiences. In agreement with previous studies, rats exposed to the uncontrollable protocol demonstrated high concentration of sera corticosterone, increased immobility, reduced duration of struggling in the forced swim test and impaired ability to acquire subsequent learning tasks. Achieving emotional controllability resulted in resilience to stress as was indicated by longer duration of struggling in the forced swim test, and enhanced learning abilities. Our prolonged training protocol, with the demonstrated ability of rats to gain emotional controllability, is proposed as a useful tool to study the neurobiological mechanisms of stress resilience.

The effects of a reminder of underwater trauma on behaviour and memory-related mechanisms in the rat dentate gyrus.

Intrusive re-experiencing is a core symptom in post-traumatic stress disorder (PTSD), often triggered by contextual cues associated with the trauma. It is not yet clear if intrusive re-experiencing is only the result, or whether it may contribute to the establishment of PTSD following acute stress. This study aimed at examining the impact of an underwater trauma (UWT) reminder on anxiety-like behaviour and on neuronal activity and plasticity in the hippocampus and the amygdala. Sprague-Dawley rats were exposed to UWT and 24 h later were re-exposed to the context. The effects on behaviour, activation of the amygdala (BLA) and dentate gyrus (DG), and on long-term potentiation (LTP) and local circuit activity (frequency-dependent inhibition (FDI) and paired-pulse inhibition (PPI)) in the DG were assessed. The exposure to UWT by itself resulted in increased anxiety behaviour in the open field, together with increased PPI. Upon exposure to the UWT reminder, an additional increase in anxiety was also observed in the EPM and in FDI. Moreover, reminder exposure resulted in impaired DG LTP and a significant BLA extracellular-signal-regulated kinases (ERK) 2 activation. In conclusion, these observed effects of exposure to a trauma reminder, following the exposure to the initial trauma, might be associated with the progression of trauma-related pathologies and the development of related disorders.

Hypothalamic corticotropin-releasing factor is centrally involved in learning under moderate stress.

The corticotropin-releasing factor (CRF) neuropeptide is found to have a pivotal role in the regulation of the behavioral and neuroendocrine responses to stressful challenges. Here, we studied the involvement of the hypothalamic CRF in learning under stressful conditions. We have used a site-specific viral approach to knockdown (KD) CRF expression in the paraventricular nucleus of the hypothalamus (PVN). The two-way shuttle avoidance (TWSA) task was chosen to assess learning and memory under stressful conditions. Control animals learned to shuttle from one side to the other to avoid electrical foot shock by responding to a tone. Novel object and social recognition tasks were used to assess memory under less stressful conditions. KD of PVN-CRF expression decreased the number of avoidance responses in a TWSA session under moderate (0.8 mA), but not strong (1.5 mA), stimulus intensity compared to control rats. On the other hand, KD of PVN-CRF had no effect on memory performance in the less stressful novel object or social recognition tasks. Interestingly, basal or stress-induced corticosterone levels in CRF KD rats were not significantly different from controls. Taken together, the data suggest that the observed impairment was not a result of alteration in HPA axis activity, but rather due to reduced PVN-CRF activity on other brain areas. We propose that hypothalamic CRF is centrally involved in learning under moderate stressful challenge. Under 'basal' (less stressful) conditions or when the intensity of the stress is more demanding, central CRF ceases to be the determinant factor, as was indicated by performances in the TWSA with higher stimulus intensity or in the less stressful tasks of object and social recognition.

Remodeling of the neuronal circuits underlying opiate-withdrawal memories following remote retrieval.

Several types of memory display time-dependent reorganization of their underlying neural substrates, but it remains unclear whether affective memories associated with drug effects also follow similar reorganization. Here, we analyzed the neural circuits reactivated by the re-exposure of former dependent rats to the withdrawal-paired environment 1month after conditioning (remote memory) as compared with recent memory (Frenois, F., Stinus, L., Di Blasi, F., Cador, M., & Le Moine, C. (2005) A specific limbic circuit underlies opiate withdrawal memories The Journal of Neuroscience, 25, 1366-1374). C-fos expression showed that the circuits involved in the retrieval of withdrawal memories are partly different when comparing recent and remote reactivation, showing that, like other type of memories, affective memories linked to opiate withdrawal undergo anatomical reorganization, with a shift from extended amygdala regions toward cortical areas.

Emotional tagging--a simple hypothesis in a complex reality.

At the psychological level, the notion that emotional events may be better remembered is a long accepted view. Its translation into neurobiological mechanisms has led to the proposal of the 'emotional tag' concept, according to which, the activation of the amygdala by emotionality would result in modulation of neural plasticity in brain regions (e.g. hippocampus) involved in forming memory of the emotional event. In line with this idea, amygdala activation (by electrical stimulation or exposure to an emotional event) has been demonstrated to affect synaptic plasticity in the hippocampus. Furthermore, the mechanisms associated with the formation of a 'synaptic tag', which is a mechanism proposed to explain the specificity of synaptic plasticity, could subserve the effects of the 'emotional tag' on synaptic plasticity in the hippocampus. The literature reviewed here supports this view but points also to additional factors that should be taken into consideration, such as intensity, duration, controllability of the emotional experience, age of exposure and relations between the emotional aspects of the experience and the event-to-be-remembered. These factors do not only affect the behavioral outcome of the stressful experience but also find their expression in variations in the neuronal and biochemical pathways that are activated, and in the way those will interact with memory formation mechanisms. While adding complexity to the notion of the 'emotional tag', taking such factors into consideration is likely to bring us closer to elucidating the neural mechanisms involved in emotional memory modulation and to our understanding of the neurobiology of associated disorders, such as PTSD.

Sigma1 receptor ligands and related neuroactive steroids interfere with the cocaine-induced state of memory.

The present series of experiments examined the involvement of the sigma(1) receptor and related neuroactive steroids in the memory state induced by a very low dose of cocaine. Using a modified passive avoidance procedure in mice, we examined whether cocaine induces state-dependent (StD) learning. Animals trained and tested with saline or the same dose of cocaine (0.1 or 0.3 mg/kg) showed correct retention, measured using two independent parameters: the retention latency and a ratio between the retention latency and the last training latency. Animals trained with cocaine (0.1 mg/kg) and tested with saline or cocaine (0.03, 0.3 mg/kg), or trained with saline and tested with cocaine, showed altered retention parameters, demonstrating that StD occurred. Therefore, cocaine administered before training produced a chemical state used as an endogenous cue to insure optimal retention. Since sigma(1) receptor activation is an important event during the acquisition of cocaine reward, we tested several sigma(1) ligands and related neurosteroids. The sigma(1) agonist igmesine or antagonist BD1047 failed to produce StD, but modified the cocaine state. Among neuroactive steroids, pregnanolone and allopregnanolone, positive modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor, produced StD. However, steroids also acting as sigma(1) agonists, dehydroepiandrosterone (3beta-hydroxy-5alpha-androsten-17-one (DHEA)), pregnenolone, or antagonist, progesterone, failed to induce StD but modified the cocaine state. Furthermore, optimal retention was observed with mice trained with (igmesine or DHEA)+cocaine and tested with a higher dose of cocaine, or with mice trained with (BD1047 or progesterone)+cocaine and tested with vehicle. This study demonstrated that: (i) low doses of cocaine induce a chemical state/memory trace sustaining StD; (ii) modulation of the sigma(1) receptor activation, although insufficient to provoke StD, modulates the cocaine state; (iii) neuroactive steroids exert a unique role in state-dependent vs state-independent learning, via GABA(A) or sigma(1) receptor modulation, and are able to affect the cocaine-induced mnesic trace at low brain concentrations.